Legendary Iron Science-Ferrology

A RESEARCHER’S THREE-DECADE JOURNEY on iron metabolism uncovers essential role of iron for life and defines “Ferrology” as a new iron-centric science.

 

Iron is both essential to life on Earth and potentially toxic. Given this paradox, evolution introduced finely-tuned regulatory pathways to maintain iron homeostasis. Although the physiological consequences of iron dysregulation have long been understood, recent discoveries have led to renewed interest in iron as both a therapeutic agent and target. Fudi Wang, a vice president at the University of South China and Qiushi Chair professor at Zhejiang University School of Medicine, China, has dedicated his career to the study of “ferrology,” which he defines as an iron-centric science that addresses fundamental questions concerning iron’s essential roles in maintaining biological functions across all living organisms. “I believe that we have only begun to reveal iron’s multiple roles in human physiology,” he says. “Truly appreciating this requires a holistic approach to its study.” Due to his ground breaking discoveries and great achievements in the iron field, Dr. Fudi Wang has been invited to deliver keynote speeches in top global universities, such as University of Oxford and University of Cambridge. 

Iron: a key matter of life and death

 

When Wang set out to understand the biology of bio-metals such as selenium, zinc, iron, manganese, and copper, he never imagined his research would culminate in a deeper understanding of how heart attacks can be fatal. In a typical attack, a blocked artery starves the heart of oxygen. This damages heart tissue, triggering symptoms, including pain and nausea. But the real damage happens after the blood returns to the heart. This so-called ischemia/ reperfusion injury (I/R injury) is the primary cause of death following a heart attack. A recently discovered iron-dependent form of programmed cell death plays a crucial role in this damage, according to research in mice models by Wang’s team.

 

Iron in biological systems takes on multiple forms, shifting between different redox potentials and cofactor roles. When iron levels become dysregulated, the cell experiences oxidative stress. The membrane-bound lipids become oxidized, compromising cellular integrity and triggering ferroptosis. Ferroptosis, this programmed cell death is also a probable culprit for the heart damage sometimes caused by a widely used chemotherapy drug, according to mice studies by the same team¹. “We knew there was a connection between the death of cardiomyocytes and several types of cardiovascular disease, but the process was a mystery,” Wang says. In a review article, Wang and his colleagues argue that iron imbalance and ferroptosis is the common denominator in many types of cardiovascular disease. “Identification of an iron-mediated form of programmed cell death allowed a more nuanced understanding of iron’s essentiality in human health and disease,” says Fudi Wang.

 

“Dr. Fudi Wang has been a leader in this field. He has used predominantly mouse models to understand the roles of this process in various systems, including the heart, liver, brain, kidney and blood. His studies have enabled significant advances in this field and have served to emphasize its importance, He has married this interest to his desire to understand how different metals influence biology, another area where he has made important contributions.” Says Dr. David Rubinsztein, who is Professor of Molecular Neurogenetics and a UK Dementia Research Institute group leader at the University of Cambridge. Rubinsztein also serve as the deputy director of the Cambridge Institute for Medical Research, has received recognition in various ways, including being elected Fellow of the Academy of Medical Sciences (2004), EMBO member (2011), Fellow of the Royal Society (2017) and member of Academia Europaea (2022).

 

“Dr. Fudi Wang has been one of the leading figures in uncovering the importance of ferroptosis in various disease processes.” Says Dr. Samira Lakhal-Littleton, who is Associate Professor of Cell Physiology at the University of Oxford.

 

Ferroptosis: an iron dependent cell death drives many diseases

 

Wang’s team has also discovered a role for ferroptosis in a hereditary iron absorption disease and liver disease³. Wang attributes his team’s contributions to insights gained from a body of work that extends from discovering new iron metabolism genes to identifying a novel mechanism for degradation of ferroportin, the body’s only way of moving iron from cells into the blood.

 

Wang and his collaborators, including Junxia Min at the Translational Medicine Institute, Zhejiang University, have spent decades at the forefront of iron and ferroptosis research. Their efforts have identified several novel key genes involved in iron homeostasis and ferroptosis. More recently, they have unpacked the mechanisms that underpin ferroptosis. In the process, they have identified a slew of new drug targets for heart, liver, and kidney diseases, and cancer. Drugs that target iron-dependent cell death could help treat a range of diseases, says Wang.

 

“Prof Dr Fudi Wang is an internationally recognized researcher in the field of iron and iron-mediated death called ferroptosis across a significant number of diseases for which he has established relevant murine models. His pioneering works in this field have clearly linked the modulation of iron and related ferroptosis in prognosis and therapy of various iron-related disorders notably cancer and a number of cardiovascular and metabolic disorders. He is renown for his work with bimetals in general, notably iron giving him internationally the label of the ‘Godfather of iron’.” Says Dr. Charareh Pourzand, a Reader (Prof W3) in Pharmaceutics, the leader at the UVA photobiology and iron/oxidative stress group at the Department of Life Sciences of the University of Bath (UK), and also the director of Innovation at the Centre for Therapeutic Innovation.

 

In health, ferroptosis helps eliminate cancer cells. Unlike other types of programmed cell death, ferroptosis depends on iron accumulating in a cell. That triggers the rapid generation of reactive oxygen species, which destroy cell membranes, killing the cell.

“Ferroptosis is a fundamental mechanism that is running in our body all the time,” says Wang.

 

Iron overload induces tissue injury

 

In 2019, the Wang team showed that iron accumulated in the heart cells of mice following I/R injury. This iron overload triggered ferroptosis and tissue damage. Critically, when they treated the mice with drugs that inhibit ferroptosis or mop up iron, I/R injury was less severe⁴.

 

The same set of mice studies revealed that doxorubicin, a drug used to treat common cancers such as breast and bladder cancer, increases the activity of a gene Hmox-1 in heart cells. The gene codes for an enzyme that breaks down the iron-carrying haem protein to release iron. That suggested that free iron causes doxorubicin-induced cardiac injury, says Wang. Further research from the team, suggests that the free iron probably wreaks its damage through ferroptosis.

 

Out-of-control ferroptosis doesn’t only play havoc with heart tissue. In an earlier study, Wang, Min and their colleagues investigated a mouse stand-in for hemochromatosis, a hereditary disorder in which iron silently accumulates, damaging joints and essential organs like the heart, liver and kidneys. Often the iron overload remains undiagnosed until middle age, by which time organs are irreparably damaged, leading to pain, diabetes, heart arrhythmias and liver cirrhosis.

 

In the mouse stand-in for hemochromatosis, iron overload triggers liver damage through ferroptosis, Wang, Min and the team reported in 2017. Their studies point to promising new targets for potential therapies.

There are plenty of target leads to follow. Ferroptosis is regulated by three interconnected pathways: one involving iron accumulation, another, lipid metabolism, and the third, the antioxidant glutathione.

 

Harnessing the three regulatory pathways is the route to combatting dangerous ferroptosis, says Wang, comparing them to the formidable warriors in the Chinese legend ‘Three heroes combating Lu Bu.’ That warrior imagery made the cover of the journal Frontiers of Medicine in April 2023 to accompany a review article by Wang, Min and another colleague⁶. Small-molecule drugs have been designed to target ferroptosis in disease, and Wang and Min are testing these in animal and clinical studies.

 

Iron emerges as a hot research area for translational application

 

Iron is an extraordinary element, according to Fudi Wang. Iron was a critical component in the formation of the earliest lifeforms, he says, and iron-based drugs are being developed for medical applications. “Iron is also critical for health, and through our most recent work we now understand that it is also central in diseases caused by a kind of cell death called ferroptosis,” says Wang.

 

Wang has studied iron and other metals for more than three decades. He has seen iron research change from a niche interest into a competitive, fast-moving field. Wang’s earlier research, including at Harvard Medical School, in the laboratory of Nancy Andrews, focused on iron metabolism. This prepared the ground for understanding the cellular mechanisms that drive ferroptosis and its significance in health and disease, says Wang.

 

“Iron didn’t attract much attention,” says Wang. “Then we unveiled a more mysterious, broader side of iron, and it has become a hot topic.”

 

Targeting iron and ferroptosis: towards novel therapeutics

 

The role of ferroptosis in human health is rapidly emerging. Wang has employed in vivo models to reveal critical mechanisms between ferroptosis and major diseases, as well as potentially valuable therapeutic targets and intervention strategies. Here are some highlights of that work.

 

• Pathways linked to ferroptotic heart disease: Identification of free iron as a driver of ferroptosis-mediated cardiomyopathy and heart failure. This was the first study to connect ferroptosis with heart disease.
• Mechanisms related to iron-induced liver disorders: Elucidation of the regulatory pathways and molecular mechanisms implicated in ferroptosis mediating liver jury and
• Role of iron in modulating acute kidney injury (AKI): Metformin exacerbates AKI by provoking renal injury by iron-dependent ferroptosis. This discovery provided mechanistic evidence that metformin damages kidneys, an area of scientific debate.
• Discovery of novel targets and drugs for treating ferroptotic diseases: Wang led his team Identified several novel iron and ferroptosis targets for the development of new therapeutics, and also developed drugs, including a phase II clinical trial class I new drug, for the treatment of beta-thalassemia and nonalcoholic steatohepatitis.

Wang’s contributions were recognized in August 2023 when he became the first Chinese researcher since 1973 to be elected to the board of directors of the International Society for the Study of Iron in Biology and Medicine. As the Founder and President of the Bio-Trace Element Society of China since 2018, his leadership has been also well-recognized and appreciated by iron society worldwide. “Professor Wang is internationally well recognized and leading. In particular, he has taken the basic science of the biochemical process forward to demonstrate its implications and applications for various diseases and new pharmacology. It is this interface of basic and applied research that generates impact and benefits world-wide as demonstrated in Prof Wang’s paper in most respected scientific journals. We have been delighted to learn about the breadth and depth of his research.” Says Dr. Wolfgang Maret, who is professor at King’s College London, a fellow of the Royal Society of Chemistry, and focusing metallomics – possibly the only professorial chair on this topic in the world.

 

“Under [Wang’s] visionary leadership, we have conducted research to target iron-dependent cell death to treat disease,” says Min. “Some of our research has made its way into clinical applications, such as iron-targeting drugs.” That illustrates why collaboration between basic, clinical and translational research is so critical, says Wang. “Collaboration allows us to leverage each other’s strengths and accelerate basic research findings into medicines that safeguard human health.”

 

Ferrology: a roadmap to decoding iron in human health and disease

 

The growing evidence of iron’s ubiquity across the landscape of human health and disease serves as motivation to establish ferrology as a dedicated field of study, he says. “Iron’s importance to the function of living organisms necessitates a focused, multidisciplinary approach to understanding the foundations of both its essentiality and toxicity,” Wang explains. “Elucidating these details to address iron-centric problems could reveal answers to a spectrum of human diseases.”

 

This story is adapted from Nature (Oct 27, 2023, https://www.nature.com/articles/d42473-023-00346-8) and Science (Oct 27, 2023, https://www.science.org/content/resource/welcome-new-iron-age) and interviewed with Dr. Fudi Wang.